Process and intermediates for preparing cephalosporin antibiotics

ABSTRACT

The silylated and enamine protected D-3- or 4-hydroxyphenylglycine as the sodium salt of the formula ##STR1## wherein A is methyl or ethyl, are crystalline intermediates useful in a new process for the acylation of heterocyclic-thiomethyl-substituted cephalosporin nuclei, e.g. 7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7-amino-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

BACKGROUND OF THE INVENTION

This invention relates to chemical intermediates useful in thepreparation of cephalosporin antibiotic compounds. It further relates toa process for the preparation of certain cephalosporin antibiotics. Inparticular, this invention relates to sodium 3- or4-(trimethylsilyloxy)-phenylglycinate as the enamine formed with methylor ethyl acetoacetate and to a process for the preparation of3-heterocyclic-thiomethyl-substituted cephalosporins such as 7-(3- or4-hydroxyphenylglycylamido)-3-(1-methyl-1H-tetrazole-5-thiomethyl)-3-cephem-4-carboxylicacid and 7-(3-or4-hydroxphenylglycylamido)-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid. The compounds prepared by the process of this invention have beenpreviously described, for example, by Ryan in U.S. Pat. No. 3,641, 021,by Dunn, et al., in U.S. Pat. Nos. 3,867,380 and 3,855,213 and by Cooperin co-pending application Ser. No. 498,886 now U.S. Pat. 3,946,003.

The trimethylsilyloxy-enamine-protected hydroxy substitutedphenylglycines described herein are useful intermediates in the processof this invention.

SUMMARY OF THE INVENTION

The sodium salt of the enamine formed with 3- or 4-hydroxyphenylglycineand methyl acetoacetate or ethyl acetoacetate is reacted undersubstantially anhydrous conditions with a trimethylsilylating agent suchas hexamethyldisilazane or trimethylsilylacetamide (MSA) to form thetrimethylsilyl ether of the hydroxyphenylglycine enamine sodium salt.The trimethylsilyl ether-enamine-salt is isolated as a crystalline whitesolid and can be stored in a dry atmosphere for future use in thepreparation of cephalosporin antibiotics. The trimethylsilylether-enamine-salt is converted to the mixed anhydride active derivativeformed with methyl or ethyl chloroformate and used in a novel process toacylate a soluble silylated derivative of a3-heterocyclic-thiomethyl-substituted 7-amino cephalosporin such as7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid or7-amino-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid. The acylation product is treated in situ with a methanolicsolution of the sodium salt of a carboxylic acid to effect thedecomposition of both the trimethylsilyl ether group of thephenylglycine side chain and the trimethylsilyl ester group of thesilylated nucleus, and to convert the acylation product to the sodiumsalt form. The sodium salt of the enamine protected product is isolatedand is treated with a mineral acid to effect the hdyrolysis of theenamine group and provide the cephalosporin antibiotic compound, forexample,7-[D-2-amino-2-(4-hyroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid or7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid.

DETAILED DESCRIPTION

This invention provides amino-protected and hydroxy-protected 3- or4-hydroxyphenylglycine compounds represented by the following formula I,##STR2## wherein A is methyl or ethyl.

The intermediates represented by the above formula are derivatives of 3-or 4-hydroxyphenylglycine in the sodium salt form wherein the aminogroup is protected as the enamine formed with methyl or ethylacetoacetate and the phenolic hydroxyl group is protected with atrimethylsilyl group. These doubly protected hydroxylated phenylglycineintermediates are useful in the preparation of cephalosporin antibioticswherein the 7-position side chain is an hydroxylated phenylglycyl group.

These cephalosporin antibiotics have been synthesized by acylating theappropriate 7-amino nucleus compound with an amino-protectedhydroxyphenylglycine. Following the acylation, the amino protectinggroup is removed to provide the anitibiotic compound. The intermediatesrepresented by formula I wherein both the phenolic hydroxyl group andthe α-amino group of the hydrolyated phenylglycine are protected byreadily removed protecting groups are uniquely suited in the preparationof these antibiotic compounds. The further protection of the phenolichydroxyl group via the trimethylsilyl group affords yield advantages aswell as improved purity of the antibiotic products when theseintermediates are used in the acylation of the appropriate 7-aminonucleus compound.

The compounds represented by formula I can be formally named asderivatives of crotonic acid, for example, 3-[[α-carboxy-3- or4-[(trimethylsilyl)oxy]benzyl]amino]]-crotonic acid, methyl ester,sodium salt. For convenience in the description of this invention, thecompounds of formula I will be referred to as the trimethylsilyl etherof 3-or 4-hydroxyphenylglycine enamine sodium salt. As used herein theterm "enamine" refers to the enamine formed with methyl acetoacetate orethyl acetoacetate.

The compounds of formula I are prepared by first converting thehydroxyphenylglycine to the sodium salt, reacting the sodium salt withmethyl or ethyl acetoacetate and recovering the crystalline enaminesalt. The salt is dried and is then reacted under anhydrous conditionswith a trimethylsilylating agent to form the crystalline trimethylsilylether of the enamine salt.

The sodium salt of the hydroxyphenylglycine is preferably perpared inmethanol as follows. A suspension of the hydroxyphenylglycine inmethanol is treated with sodium hydroxide pellets and the mixture heatedat a temperature of about 60° C. for about 15 minutes. The sodium saltof the acid forms a thick slurry in methanol.

The salt is then converted to the enamine as follows. Methyl or ethylacetoacetate is added to the slurry and the mixture heated at the refluxtemperature for about 1 to 2 hours. A clear solution of the enaminesodium salt forms. With continued reflux, acetonitrile is added to thesolution and the methanol is allowed to distill off. The reactionmixture is allowed to cool to room temperature with stirring and theproduct enamine salt which crystallizes is colleced and dried. The driedenamine salt is then added portionwise to a solution of thetrimethylsilylating agent in acetonitrile maintained in a dryatmosphere, for example, dry nitrogen. The mixture is warmed to atemperature of about 50° C. with stirring. Additional acetonitrile isperiodically added to the thick slurry to maintain the mixture at astirrable consistency. The reaction mixture is then cooled to atemperature of about 20° C. and the product is filtered in an atmosphereof dry nitrogen.

Silylating agents which can be employed in the preparation of thecompounds of formula I include, for example,monotrimethylsilylacetamide, hexamethyldisilazane, N-trimethylsilylsuccinimide, trimethylsilyl methylamine, and like silylating reagents.Bis-trimethylsilyl acetamide can also be employed; however, it impartsorange coloration to the reaction mixture making the purification of thetrimethylsilyl ether enamine salt difficult. From an economic standpointthe preferred silylating agent is hexamethyldisilazane.

The trimethylsilyl ethers of the 3-or 4-hydroxyphenylglycine enaminesodium salts are crystalline white compounds which are stable whenstored away from contact with moisture.

According to a further aspect of this invention, the trimethylsilylethers of formula I are used in an improved acylation process for thepreparation of cephalosporin antibiotic compounds represented by thefollowing formula II ##STR3## wherein R represents a 5-memberedheterocyclic ring substituent selected from the group consisting of##STR4##

According to the process of this invention, the trimethylsilyl ether ofthe 3- or 4-hydroxyphenylglycine enamine sodium salt is converted to theactive acylating agent by reaction with methyl or ethyl chloroformate toform the mixed anhydride represented by the formula ##STR5## wherein Aand A' are methyl or ethyl.

The trimethylsilylated enamine mixed anhydride is then used in the firststep of the process in the acylation of a silylated7-amino-3-heterocyclic-thimethyl substituted cephalosporin nucleuscompound represented by the formula ##STR6## wherein R has the samemeanings as defined above.

The acylation product is represented by the following formula ##STR7##The intermediate trimethylsilyl ether enamine-protected acylationproduct as the trimethylsilyl ester represented by the above formula isconverted in situ to the sodium salt by adding to the reaction mixture asolution of a sodium salt of a carboxylic acid in methanol. Thetreatment also affects the decomposition of the trimethylsilyl ethergroup and the trimethylsilyl ester group while the enamine protectinggroup remains intact. The de-silylated enamine-protected acylationproduct as the sodium salt represented by the following formula ##STR8##is readily isolated as a stable crystalline solid under the conditionsemployed in the process of this invention.

The enamine salt of the above formula is then hydrolyzed with a mineralacid in an aqueous medium to effect the removal of the enamineprotecting group and provide the antibiotic compound.

Illustrative 7-amino-3-heterocyclic-thiomethyl substituted nucleuscompounds used in the process of this invention are7-amino-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid,7-amino-3-(5-methyl-1,3,4-oxadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid, 7-amino-3-(1,2,3-triazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid, and7-amino-3-(1,5-dimethyl-1,3,4-triazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid.

As noted above, the trimethylsilyl ether of the 3-or4-hydroxyphenylglycine enamine sodium salt represented by formula I isconverted to the mixed anhydride formed with methyl or ethylchloroformate for use as the active acylating agent. The mixed anhydrideis prepared as follows. The trimethylsilyl ether enamine sodium salt isadded with stirring to a solution of trimethylsilyl succinimide inacetonitrile and the thick slurry is cooled to a temperature of about-35° C. by means of an acetone/dry ice bath. A small amount ofdimethylbenzylamine is added to the cold slurry and a slight excess ofmethyl or ethyl chloroformate is slowly added. As the mixed anhydrideforms, the slurry thins and sodium chloride precipitates from thesolution. The preparation of the mixed anhydride is carried out in a dryatmosphere, for example, under dry nitrogen.

The mixed anhydride of the trimethylsilyl ether enamine sodium salt isthen employed without isolation in the acylation process of thisinvention which is carried out as follows.

Initially, the 3-heterocyclic-thiomethylsubstituted 7-aminocephalosporin nucleus is converted to a soluble silylated derivative foracylation. The silylated derivative of the 7-amino nucleus compound isprepared by suspending the nucleus in acetonitrile and adding to thesuspension at about room temperature a 3-molar excess of trimethylsilylacetamide. The mixture is stirred at ambient temperature until solutionis complete. The solution is then cooled to a temperature of betweenabout -15° to -20° C. The silylation of the 7-amino nucleus compound iscarried out under substantially anhydrous conditions which areconveniently maintained in an atmosphere of dry nitrogen.

According to the process of this invention the silylated 7-amino nucleuscompound is acylated with the mixed anydride of the trimethylsilyl etherenamine at a temperature between about -50° and 0° C. and preferably atabout -25° to about -5° C. The acylation is carried out by slowly addingthe cold solution of the silylated 7-amino nucleus compound in a drynitrogen atmosphere to the solution of the mixed anhydride of the silylether of the 3- or 4-hydroxyphenylglycine enamine prepared as describedabove. The acylation mixture is stirred and is allowed to warm to atemperature of about -5° C. over a 1 to 2 hour period. The reactiontemperature is then maintained at about -5° C. until the reaction iscomplete.

The soluble silylated-enamine-protected acylation product is nextconverted to the insoluble sodium salt free of silylated functionalgroups as follows. The acylation reaction mixture is optionallyfiltered, preferably with a filter aid and the light yellow filtrate isallowed to warm to about 20° C. A solution of a sodium salt of a C₂ -C₁₀alkyl carboxylic acid in methanol is added to the warmed filtrate withstirring. Meanwhile, a low vacuum is applied to the mixture which iswarmed to a temperature of about 30°-35° C. to remove the volatiletrimethylsilyl side products formed with methanol. With continuedstirring, the enamine protected acylation product (formula III)precipitates from the filtrate as the sodium salt. The mixture is cooledto a temperature of about 20° C., is filtered and the salt washed withacetonitrile and with anhydrous ether. A dry nitrogen atmosphere ismaintained over the filtration. The product, which is generallysolvated, is dried in vacuo or preferably in a dry nitrogen atmosphere.

Sodium salts of carboxylic acids which can be employed in the process ofthis invention include the sodium salts of carboxylic acids which areless acidic than the C₄ carboxylic acid group of the cephalosporinproduct. Such salts include, for example, sodum acetate, sodiumpropionate, sodium butyrate, sodium 2-ethylhexaoate, sodium octanoateand like salts. The preferred sodium salt is sodium 2-ethylhexanoate.

The dried sodium salt of the enamine-protected-acylation product is thenhydrolyzed in an aqueous medium under acidic conditions to remove theenamine protecting group to provide the antibiotic compound representedby formula II.

The acidic hydrolysis of the compound of formula III is carried out inaqueous media consisting of water and a water miscible aprotic organicsolvent. Solvents such as acetonitrile, tetrahydrofuran, dioxane,dimethylformamide and dimethylacetamide are examples of solvents whichcan be used with water in the process. A preferred solvent is aqueousacetonitrile.

The acidic hydrolysis is carried out as follows. The dry enamine salt isdissolved in acetonitrile:water (3:1, v:v) at a temperature of about 50C. Complete solution occurs within a few minutes. Mineral acid is addeddropwise to the warm solution until the pH is adjusted to between about4.0 to about 6.5. The deblocked product begins to precipitate at a pH ofabout 6.5. The temperature of the solution is maintained at about 50° C.until the pH adjustment and crystallization are complete. The mixture isthen cooled to about 10° C. and the product is collected by filtration.The product is washed with a mixture of acetonitrile and water andfinally with acetonitrile alone to wash the product free of the coloredfiltrate. The product can be further decolorized by resuspending thecrystalline precipitate in a mixture of acetonitrile:water or otheraqueous solvent and refiltering. The crystalline antibiotic can be driedin air or in vacuo to constant weight.

The acid hydrolysis of the enamine sodium salt described above ispreferably carried out with nitric acid; however, other mineral acidssuch as hydrochloric acid and sulfuric acid can be employed.Hydrochloric acid is less preferred since the sodium chloride formed ontreatment of the enamine protected cephalosporin salt with the acidcauses phase separation of the mixture, thus rendering the isolation ofthe precipitated product more difficult.

The process of this invention provides excellent yields of high qualitycrystalline products. The use of the trimethylsilyl protected 3- or4-hydroxyphenylglycine enamine as described in this process greatlyminimizes the formation of side products formed by virtue of theacylation of an unprotected 3- or 4-hydroxy group of the phenylglycinemoiety. Under the substantially anhydrous conditions of this process,the trimethylsilyl ether group remains intact until decomposed withmethanol following the acylation.

The following hydroxyphenylglycylamido cephalosporin antibiotics areprepared by the process of this invention.

7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid,

7-[D-2-amino-2-(3-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid,

7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid,

7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-oxadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid,

7[D-2-amino-(4-hydroxyphenyl)acetamido]-3-(1,2,3-triazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid, and

7-[D-2-amino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid.

In a preferred embodiment of the process of this invention, thetrimethylsilyl ether of the enamine protected 4-hydroxyphenylglycinesodium salt is converted to the mixed anhydride with methylchloroformate and is used to acylate the trimethylsilylated7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid. The intermediate silylated-enamine-protected acylation product istreated with a methanolic solution of sodium 2-ethylhexanoate todecompose the silyl protecting groups and to precipitate the enamineprotected acylation product as the sodium salt. The sodium salt is thendissolved in a mixture of acetonitrile and water as described above andis acidified with concentrated nitric acid to a pH of about 4.7 . Theproduct,7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid, precipitates from the acidified hydrolysis mixture.

This invention further provides an improved process for the acylation ofa 7-amino-3-(heterocyclic-thiomethyl)-3-cephem-4-carboxylic acids of theformula, ##STR9## wherein R has the same meanings as defined in formulaII, which comprises acylating the nucleus with the mixed anhydride ofthe compound represented by the formula 1 formed with methyl or ethylchloroformate. The mixed anhydride of the compound of formula Icomprising the trimethylsilyl protecting group and the enamineprotecting group permits the acylation to be carried out withoutcompeting acylations involving an unprotected phenolic hydroxy group.Acylation with an active derivative of an enamine-protectedhydroxyphenylglycine without an hydroxy-protecting group leads to theformation side products formed by the acylation of the free hydroxygroup of the acylating agent itself, thus lowering the yield of thedesired N-acylated cephalosporin as well as complicating its isolationand purification.

This invention is further illustrated by the following detailedexamples.

EXAMPLE 1

To a suspension of 23.9 g. (0.143 M) of D-4-hydroxyphenylglycine in 150ml. of methanol were added 6 g. (ca. 0.145 M) of sodium hydroxidepellets. The mixture was heated at 60° C. with stirring for about 15minutes during which time the sodium salt of the acid formed a thickslurry. To the slurry were added 20.1 ml. (0.186 M) of methylacetoacetate and the mixture was heated at the reflux temperature ofapproximately 68° C. for 90 minutes. After about 20 minutes at thereflux temperature, a clear solution was obtained and following 20additional minutes, the product began to crystallize from the clearsolution. With continued heating at the reflux temperature, 300 ml. ofacetonitrile were added dropwise over a 15 minute period. Thereafter,the solvent methanol was allowed to distill out of the mixture whileanother 300 ml. of acetonitrile was added dropwise over approximately 75minutes. The reaction mixture was allowed to cool to room temperaturewith continued stirring. The crystalline product precipitated at roomtemperature, was filtered and washed with approximately 200 ml. ofacetonitrile. The product, the sodium salt of the methyl acetoacetateenamine of D-4-hydroxyphenylglycine, was dried to yield 40 g. of white,crystalline solid (97 percent yield).

EXAMPLE 2

To a solution of 160 ml. (d= 0.774) of hexamethyl disilazane in 250 ml.of acetonitrile in a 3-liter, round bottom, 3-necked flask equipped witha stirrer, thermometer, heating mantle, reflux condenser and a drynitrogen purge were added 216 g. of finely ground methyl acetoacetateenamine of p-hydroxyphenylglycine sodium salt prepared as described inExample 1. The mixture was warmed to a temperature of about 50°-55° C.with stirring and two drops of trimethylsilyl chloride were added to thethick slurry. Additional acetonitrile totaling 1750 ml. was addedperiodically to maintain a stirrable consistency. The mixture was keptat 50°-60° C. for about 8 hours and was then cooled to about 20° C. andfiltered in an atmosphere of dry nitrogen. The fine white crystallineproduct was washed with 600 ml. of acetonitrile and 1000 ml. ofanhydrous diethyl ether. Trimethylsilylsuccinimide was added to eachwash solvent to about a 1 percent concentration to protect thetrimethylsilyl group from possible hydrolysis due to any trace amountsof water. The product was dried in an atmosphere of dry nitrogen andstored in a closed container. The weight of dried product was 256 g.

Elemental analysis calculated for C₁₆ H₂₂ NO₅ SiNa: Theory: C, 53.46; H,6.17; N, 3.90; O, 22.26. Found: C, 52.98; H, 6.37; N, 4.07; O, 21.15.

NMR, T60 (DMSO d₆)*: δ

0.08, 0.23 (9H, two singlets), 1.67 (3H, s), 3.51 (3H, s), 4.28 (1H, s),4.75 (1H, d, J= 7Hz), 6.74 (2H, d, J= 8Hz), 7.21 (2H, d, J= 8Hz), and9.60 (1H, d, J= 7Hz)

EXAMPLE 37-[D-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid

To a dry 5-liter round bottom, 3-necked flask equipped with a stirrer, acooling bath, a low temperature thermometer, and a dry nitrogen purgeare added one liter of dry acetonitrile and 15 g. (87 mM) oftrimethylsilyl succinimide. To the solution are added with stirring 256g. (715 mM) of the trimethylsilyl ether of 4-hydroxyphenylglycineenamine sodium salt prepared as described by Example 2. The thick whiteslurry which is obtained is cooled to -35° C. by means of an acetone/dryice bath; 2 ml. of dimethylbenzylamine are added, and 60 ml. of methylchloroformate (d= 1.223, 97 percent) are added in a slow stream over 3to 5 minutes. The white slurry thins out considerably as the mixedanhydride forms and sodium chloride precipitates from the reactionmixture. The solution of the mixed anhydride is stirred at a temperatureof about -35° C. for 20 minutes before a cold solution of thetrimethylsilylated7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid in acetonitrile is added. The solution of the silylated7-amino-nucleus compound is separately prepared for the acylation asfollows.

To a dry 2-liter round bottom, 3-necked flask equipped with a stirrer, alow temperature thermometer, a cooling bath, and a dry nitrogen purgeare added 250 ml. of dry acetonitrile, 263 g. (1800 mM) oftrimethylsilyl acetamide (90 percent pure), and 215 g. (600 mM) of7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid (96 percent pure). The mixture is stirred at room temperature untilsolution is complete, usually within 40 minutes. Just before addition tothe mixed anhydride, the solution is cooled to a temperature betweenabout -15° and -20° C. by means of an acetone/dry ice bath.

The cold solution of the silylated 7-amino nucleus compound is thensiphoned into the cold solution of the mixed anhydride prepared asdescribed above. The reaction mixture is then allowed to warm to atemperature of about -5°0 C. over about 2 hours. Approximately 600 ml.of Hyflo filter aid is added to the reaction mixture with stirring andthe reaction mixture is filtered through a Hyflo filter pad into a5-liter round bottom, 3-necked flask, maintained under a dry nitrogenatmosphere. The filter is washed with dry acetonitrile and the lightyellow filtrate is warmed to 20° C. with gentle stirring. The solutionis seeded with crystalline sodium7-[D-2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylate,the desilylated enamine protected acylation product. A slight vacuum isapplied to the seeded solution while 316 ml. of a 1.9 molar solution ofsodium 2-ethylhexanoate in dry methanol is added over approximately 5minutes. The vacuum is maintained to remove the volatile silyl productsand the temperature of the solution is increased to about 30°-35° C. Thedesilylated enamine protected acylation product as the sodium saltbegins crystallizing from the mixture and after approximately 2-3 hours,the temperature of the crystalline mixture is reduced to 20° C. and isfiltered. The crystalline product is washed with dry acetonitrile andwith anhydrous ether. A dry nitrogen atmosphere is maintained over thefiltration. The granular, heavily solvated solid is dried in vacuo toyield 354 g. (96 percent) of the sodium salt of the enamine protectedacylation product.

Physical characteristics:

(UV (MeOH) λmax 283 (36,000), 232 (16,500)

]α]_(D) ²⁵° C = +65.2° (DMSO)

I.R. (mull) β-lactam 1760 cm⁻¹, amide 1664, other carbonyls 1590-1630N.M.R. (DMSO d₆) δ 1.75 (3H, 2), 2.64 (3H, s), 3.31 (1H, d, J= 17.5 Hz),ca. 3.4 (1H, broad), 3.51 (3H, s), 3.52 (1H, d, J= 17.5 Hz), 4.35 (1H,d, J= 12.5 Hz), 4.45 (1H, s), 4.50 (1H, d, J= 12.5 Hz), 4.89 (1H, d, J=5 Hz), 5.38 (1H, d, J= 8 Hz), 5.53 (1H, d of d., J= 5, 8 Hz), 6.74 (2H,d, J= 9 Hz), 7.17 (2H, d, J= 9 Hz), 9.20 (1H, d, J= 8 Hz), 9.26 (1H, d,J= 8 Hz).

One liter of a solvent mixture of acetonitrile:water (3:1, v:v) is addedto a 2-liter beaker and warmed to a temperature of about 50° C. Withstirring, 307 g. of the enamine protected sodium salt prepared asdescribed above are added to the warm solution with stirring. Completesolution occurs in a few minutes. The initial pH of the solution isapproximately 7.7. The pH of the solution is adjusted to 4.7 by thedropwise addition of concentrated nitric acid. The solution ismaintained at a temperature of 50° C. until crystallization of theproduct is complete. Thereafater, the mixture is slowly cooled over 1-2hours to a temperature of about 10° C. The crystalline product,7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylicacid, is collected by filtration and is washed thoroughly with coldsolvent (acetonitrile:water 3:1) and also with acetonitrile. The productis dried in air or, alternatively, in vacuo to a constant weight. An 84percent yield of product, (208 g.) is obtained. When the product isobtained as a very fine crystalline precipitate, the product is bestwashed by resuspension in fresh solvent mixture and refiltration.

I claim:
 1. A 3- or 4-(trimethyl)silyl ether of an amino-protectedphenylglycine salt of the formula ##STR10## wherein A is methyl orethyl.
 2. The compound of claim 1 wherein A is methyl.
 3. The compoundof claim 2 said compound being the 4-(trimethyl)silyl ether.